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| Status |
Public on Jun 01, 2013 |
| Title |
Inhibition of dihydroorotate dehydrogenase by doxorubicin and brequinar sensitize cancer cells to TRAIL-induced apoptosis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent in selectively killing tumor cells. However, TRAIL monotherapy has not been successful as many cancer cells are resistant to TRAIL. Chemotherapeutic agents, such as doxorubicin have been shown to act synergistically with TRAIL, but the exact mechanisms of actions are poorly understood. In this study, we performed high-throughput small interfering RNA screening and genome-wide gene expression profiling on doxorubicin-treated U1690 cells to explore novel mechanisms underlying doxorubicin-TRAIL synergy. The screening and expression profiling results were integrated and dihydroorotate dehydrogenase (DHODH) was identified as a potential candidate. DHODH is the rate-limiting enzyme in the pyrimidine synthesis pathway, and its expression was downregulated by doxorubicin. We demonstrated that silencing of DHODH or inhibition of DHODH activity by brequinar dramatically increased the sensitivity of U1690 cells to TRAIL-induced apoptosis both in 2D and 3D cultures, and was accompanied by downregulation of c-FLIPL as well as by mitochondrial depolarization. In addition, uridine, an end product of the pyrimidine synthesis pathway was able to rescue the sensitization effects initiated by both brequinar and doxorubicin. Furthermore, several other cancer cell lines, LNCaP, MCF-7 and HT-29 were also shown to be sensitized to TRAIL by brequinar. Taken together, our findings have identified a novel protein target and its inhibitor, brequinar, as a potential agent in TRAIL-based combinatorial cancer therapy and highlighted for the first time the importance of mitochondrial DHODH enzyme and pyrimidine pathway in mediating TRAIL sensitization in cancer cells.
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| Overall design |
Total RNA obtained from small cell lung cancer U1690 cells either treated with DMSO control or 1 µM doxorubicin for 12 or 24h.
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| Contributor(s) |
He T, Haapa-Paananen S, Kohonen P, Perälä M |
| Citation(s) |
24013224 |
| Submission date |
Nov 27, 2012 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Tao He |
| E-mail(s) |
tao.he@vtt.fi
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| Organization name |
VTT
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| Street address |
Itäinen Pitkäkatu 4C
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| City |
Turku |
| ZIP/Postal code |
20521 |
| Country |
Finland |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA182213 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE42531_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE42531_non_normalized.txt.gz |
2.6 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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